The incidence of diabetes is increasing at an alarming rate both nationally and worldwide with approximately two million new cases diagnosed every year in the US alone, with nearly 9 out of 10 new cases due to type 2 diabetes melitus (t2DM). Diabetes population and related costs are expected to at least double in the next quarter century, as more than 80 million Americans are at risk of developing t2DM. In clinical trials, pharmacotherapy as an adjust to lifestyle changes has been successful for treating t2DM, nonetheless adherence is often poor and drug-related costs are escalating; therefore, identification of alternative therapeutic options that can be applied at the public healh level is urgently needed to decrease t2DM-related burden. Based on NIH-funded research from our group and others, suboptimal vitamin D status has emerged as a potential contributor to the pathophysiology of t2DM. However, because of potential confounding in observational studies and lack of data from adequately powered trials designed for glycemic and other metabolic outcomes, it remains unclear whether vitamin D has a clinical role in patients with established t2DM. The goal of this renewal application for a New Investigator R01, which directly extends our work in this area conducted during the first funding cycle, is to evaluate whether vitamin D is an effective non-pharmacologic nutritional intervention for t2DM. The central hypothesis is that suboptimal vitamin D status worsens glycemia in t2DM and that raising one's 25OHD concentration with vitamin D supplementation improves glycemia and other metabolic outcomes in patients with established t2DM, through improvements in insulin secretion and sensitivity. A secondary hypothesis is that the effect of vitamin D is modified by specific Vitamin D Receptor (VDR) polymorphisms. We plan to test our central hypothesis and accomplish the goals of this application by conducting a 1-year long randomized, double-masked, placebo-controlled trial of vitamin D3 supplementation in persons with established t2DM of mild/moderate severity. Declining vitamin D status is a consequence of our altered lifestyle and its strong association with t2DM, after adjusting for other lifestyle factors (weight, diet), makes the proposed study very important and timely and also consistent with national research priorities as the study is expected to fill a fundamental knowledge gap which fuels the current intense controversy in relation to the development of recommendations for vitamin D supplementation for non-skeletal medical conditions. PUBLIC HEALTH RELEVANCE: Relevance of the proposed project to public health: The proposed study addresses alternative therapeutic options for an important public health problem, type 2 diabetes. If the favorable association between vitamin D status and type 2 diabetes that have been reported in observational studies is confirmed in the clinically relevant trial, we propose, vitamin D can assume its proper role alongside established therapies to treat type 2 diabetes in the more than 26 million Americans with the disease. Relevance of the proposed project to the mission of the NIH (NIDDK and the Office of Dietary Supplements [ODS]): The research addresses important health issues of relevance to both NIDDK and ODS. Nutrition and type 2 diabetes are two obvious areas of interest to NIDDK while vitamin D is a nutrient of significant interest to ODS. Indeed, as stated in its strategic planning for 2010-14, te ODS is leading a Vitamin D Initiative, which is an evolving partnership with NIH institutes and centers and other federal agencies to fund research that address gaps in knowledge, as identified by the 2011 Institute of Medicine report on Dietary Reference Intakes for calcium and vitamin D.